The present invention relates to a method for finding nucleotide synthesis inhibitors which have lower side effects and their use in treating immunological diseases.
A fundamental problem of new medications is the relationship between tolerability and efficacy. The therapeutic window is the range between which an efficacious dose of a substance can be administered and a dose at which undesired side effects to a patient begin to occur. Generally, the larger the difference between the efficacious dose and the dose at which side effects begin to occur, the more harmless the administration of the substance and the more tolerable the substance is for the patient.
According to previous experience, cytostatic medications, including purine and pyrimidine synthesis inhibitors, have relatively narrow therapeutic windows. In addition, these medications induce side effects in a patient as a result of their main action; the suppression of the proliferation of cells. This property interferes more in the treatment of immunologically related diseases than in the treatment of oncological indications. Therefore, the use of cytostatic medications for the treatment of immunological diseases is restricted considerably.
Compounds which inhibit purine or pyrimidine synthesis are called nucleotide synthesis inhibitors (Burkhardt and Kalden; Rheumat. Int. (1997); 17: 85-90). These include, for example N-(4-trifluoromethylphenyl)-5methylisoxazole-4-carboxamide, N-(trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide, 2-cyano-3-cyclopropyl-3-hydroxyacrylic acid (4-cyanophenyl)amide or N-(trifluoromethylphenyl)-2-cyano-3-hydroxyhept-2-en-6-ynecarboxamide, brequinar(6-fluoro-2-(2xe2x80x2-fluoro[1,1xe2x80x2biphenyl]-4-yl)-3-methyl-4-quinolinecarboxylicacid), mycophenolate mofetil ((E)-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)--4-methyl-4-hexenoate), methotrexate (CAS No. 59-05-02), and mizoribine (CAS No. 50924-49-7).
Nucleotide synthesis inhibitors are beneficial to the treatment of immunologically related diseases such as rheumatoid arthritis or pemphigus vulgaris.
Disadvantages to the use of known nucleotide synthesis inhibitors include side effects such as problems relating to the gastrointestinal tract, bone marrow, and hair, etc. Slight side effects of these compounds are often only first discovered very late in the clinical development of a new medication. This sometimes leads to the discontinuation of development of these medications.
This invention takes advantage of an observed reduction in side effects of nucleotide synthesis inhibitors in the treatment of immunological diseases. This reduction occurs when the nucleotide synthesis inhibitors only briefly reach the target in the body, which is sited intracellularly, and then, within a short time, fall to concentrations that no longer inhibit nucleotide biosynthesis. By means of this measure, it is possible in the treatment of immunological diseases to reduce the side effects of nucleotide synthesis inhibitors drastically without having to accept losses in the desired action on the immune system.
With this knowledge, it is possible within a short time to develop nucleotide synthesis inhibitors which exhibit a very good efficacy in the treatment of immunologically related diseases with a very low side effect rate.
The present invention relates to a method for finding nucleotide synthesis inhibitors which have lower side effects by determining the therapeutic window expected of cytostatic medications used in the treatment of immunological indications with the aid of a technically easily measurable property. This measurement can be used to determine the therapeutic window at even an early phase of development of these substances in pharmaceutical research.
The measurement is determined by calculating the half-life of a nucleotide synthesis inhibitor in the blood of a mammal, which is relevant for pharmacokinetic ratios in humans, or in humans in phase I clinical trial development, and comparing it with that of a known nucleotide synthesis inhibitor. The term xe2x80x9chalf-lifexe2x80x9d is understood as meaning the time in which the concentration of the nucleotide synthesis inhibitor in the blood plasma is halved. This invention for finding nucleotide synthesis inhibitors which have lower side effects therefore includes
a) determining an efficacious dose of a nucleotide synthesis inhibitor in a mammal
b) administering the nucleotide synthesis inhibitor in with efficacious dose to a mammal,
c) determining the concentration of the nucleotide synthesis inhibitor in the blood of the mammal, and
d) determining whether the nucleotide synthesis inhibitor has a half-life which is shorter than that of N-(-4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide.
Suitable mammals for carrying out pharmacokinetic comparison investigations include, but are not limited to, mice, rats, rabbits, dogs, monkeys or pigs. The half-life of the nucleotide synthesis inhibitor is preferably determined in humans. Depending on the animal and nucleotide synthesis inhibitor employed, the half-lives are very different. The half-life of N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide is, for example, approximately 4 to 8 hours in rats and up to 350 hours in humans. Preferred nucleotide synthesis inhibitors are those which have a half-life of less than 150 hours, preferably less than 40 hours, in the blood plasma of humans.
The advantage of the present invention is that a statement of the expected therapeutic window of a nucleotide synthesis inhibitor being tested can be rapidly determined at a very early stage in pharmaceutical development via the measurement of the half-life in the blood plasma. Otherwise, the clinically utilizable dose range of a medicament is identified only by extensive clinical investigations with a therapy period of weeks or years. Therefore, a considerable acceleration in the development of the pharmaceutical is therefore possible.
The following examples illustrate that substances having a short half-life are preferable to substances having a long half-life in achieving the desired action of nucleotide synthesis inhibitors on the immune system with minimal side effects.